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Lentiviral vectors may offer a safe way of delivering gene therapy in humans, according to a study in this week's Proceedings of the National Academy of Sciences. In phase I clinical trials with five HIV-positive patients, researchers found that an HIV-based lentiviral vector was a safe and potentially effective way to deliver an anti-HIV gene.

"This is exactly what the field needs to see as a first step towards using these vectors in humans," said Paul McCray of the University of Iowa in Iowa City, who was not involved in the study.

Using lentiviruses such as HIV as vectors for gene therapy may avoid problems that have surfaced with conventional retrovirus vectors, said study leader Bruce Levine of the University of Pennsylvania in Philadelphia. Some retroviral vectors have inserted into oncogene promoters and caused Cancer in treated patients, but lentiviruses tend not to integrate in these promoter regions.

In previous preclinical studies, Levine and his colleagues at VIRxSYS Corporation in Gaithersburg, Md., constructed a lentiviral vector from a clone of HIV, which was gutted to remove HIV regulatory genes. They inserted a long antisense sequence against the HIV envelope and found that this sequence inhibited HIV replication in T cells.

For phase I clinical trials, the researchers studied the effects of this vector in five HIV-positive men who had become resistant to standard antiviral treatments. They removed T cells from each patient, modified the cells with the lentiviral vector, and injected one dose of the modified T cells back into the patient. The subjects were then monitored for signs of toxicity and immunological responses.

One safety concern with using lentiviruses as gene delivery vectors is that they might form replication-competent lentiviruses, but Levine and his colleagues found no evidence of this in any of the patients. Another concern is vector mobilization, which the researchers saw in the first 60 days after injection, but not after that. This mobilization probably doesn't mean the vector isn't safe, said Richard Sutton of Baylor College of Medicine in Houston, who was not involved in the study, but he acknowledged that it is "a little bit concerning. Usually we don't like these vectors to jump around once they're inside a person."

The researchers found no evidence that the vector integration sites caused any mutations that could lead to cancers. This makes sense, said John Rossi of City of Hope in Duarte, Calif., who was not involved in the study, because HIV itself has never been shown to cause cancer as a consequence of integration.

Although the primary objective of the study was to demonstrate vector safety, the researchers also found evidence that the antisense envelope sequence improved the health of some of the patients. After experiencing an initial rise in viral load, three patients showed some evidence of lowered viral load over six months or more, and four patients had increased T cell counts after one year.

"We were startled, actually," Levine said, regarding the signs of efficacy. "This is the first human trial, designed in fairly advanced patients, really only with the goals of safety and feasibility."

According to Sutton, however, the researchers do not have convincing proof of efficacy. Only one patient showed a drop in viral load that clinicians would consider important, Sutton said, and even that "could be unrelated to the infusion." Also, the increase in T cell counts that the researchers saw is sometimes seen "even in the absence of effective therapy."

The researchers also found evidence of sustained presence of modified T cells in the patients' bodies, but only two of the five patients had detectable levels of modified T cells after one year. "It's hard to imagine how this vector would have that effect if the cell-marking frequency is that low," Sutton told The Scientist. "I'm actually not convinced that there's any efficacy here. Of course, that wasn't their endpoint."

According to McCray, seeing "some improvement, even if it's transient, is encouraging," especially since the patients studied are "some of the more recalcitrant HIV patients."

Since the vector appears to be safe, Levine and his colleagues will move to phase II trials to study directly the vector's efficacy when given in multiple doses in a larger number of patients. They will also continue to follow these five patients for 15 years, to ensure that the therapy produces no adverse effects.

Finding no obvious safety problems with lentiviral vectors in this study is encouraging for their potential use in treating other diseases, Rossi said. "I see it as a very safe way of going," he told The Scientist. "I don't see any reason not to proceed forward with lentiviral vectors in gene therapy."